Chronic renal failure has major detrimental effects on male reproductive function, with renal failure, dialysis, and transplantation influencing all levels of the hypothala-mic-pituitary-testicular axis (1,2). Although the nonreproductive clinical features of uremia usually overshadow the impaired sexual function, virilization, and infertility of chronic renal failure, comprehensive medical care requires a knowledgeable and empa-thetic appreciation of men's valued, but often unstated, expectations of their reproductive health. This chapter reviews the clinical basis for and role of androgen therapy as an adjunct to standard medical care in chronic renal failure.
Androgen therapy may be considered physiological (replacement therapy) or supra-physiological (pharmacological therapy). The former is restricted to the physiological androgen (testosterone) at replacement doses aiming to replicate physiological blood testosterone concentrations. By aiming to replicate and not exceed physiological endogenous androgen exposure, replacement therapy is expected to have a safety profile comparable to the lifelong experience of eugonadal men. The restriction to testosterone, in theory, precludes use of synthetic designer androgens, which feature
From: Male Hypogonadism: Basic, Clinical, and Therapeutic Principles Edited by: S. J. Winters © Humana Press Inc., Totowa, NJ
tissue-specific activation and whose spectrum of activity may differ from testosterone. In contrast, pharmacological androgen therapy aims to use any androgen with the dosage optimized to provide maximal effects on androgen-responsive tissues within acceptable safety limits, ultimately judged by the rigorous criteria of efficacy, safety, and cost-effectiveness applicable to any nonhormonal drug. Evaluating the pharmacological role of androgens requires interventional clinical studies featuring randomization, placebo controls, and key design features, such as adequate power, duration, and validated, objective end points. Few published studies fulfill these requirements, with most comprising observational and mechanistic studies so that unequivocal therapeutic implications are limited.
The goals of androgen therapy in renal failure should be considered in relation to the natural history and current standard treatment of the disorder. Because complete androgen deficiency from early life does not reduce life expectancy (3), it is unrealistic to expect that physiological androgen replacement therapy per se can alter mortality. However, pharmacological androgen therapy may modify the natural history of chronic renal failure, and these effects may vary according to the concurrent standard therapy (e.g., renal transplantation and peritoneal vs. hemodialysis). Evidence from controlled clinical trials of androgen therapy in renal failure is highlighted with a focus on men, because pharmacological androgen therapy in women and children risks virilization or growth limitation, respectively. Currently, anemia and nutritional status are the only established indications for pharmacological androgen therapy in uremia. More recently, the availability of recombinant human erythropoietin (EPO) for treatment has greatly limited use of androgen therapy. Although there is a growing recognition of the lower costs, as well as the equivalent efficacy, and synergistic interaction with EPO has resulted in a re-examination of the role of androgen therapy in chronic renal failure. Deteriorating nutritional status in patients on dialysis, notably markers such as serum albumin (A15) and lean body mass, independently predict mortality in prospective studies (4), as well as morbidity and mortality in cross-sectional studies (5,6). Small retrospective (7) and uncontrolled (8) and controlled (9) prospective studies in patients on dialysis confirm that these markers are androgen responsive. Hence, it is possible that androgens, by increasing lean mass and promoting protein anabolism, could prolong life expectancy in patients on dialysis, particularly those undergoing peritoneal dialysis (10). The longer term safety of pharmacological androgen therapy regarding the natural history of cardiovascular and prostate disease must be considered, but is beyond the scope of this review (11).
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